Summary of Work: Reconstituted high-density lipoprotein (R-HDL) has been shown in vitro and in vivo to have anti-endotoxin properties. The hypothesis is that lipoproteins bind, neutralize, and increase clearance of endotoxin. Being a natural biological product, R-HDL could be used prophylactically to prevent septic shock in high-risk patients and in chemotherapy-induced neutropenia or therapeutically to treat septic shock. To test this hypothesis in a controlled, randomized trial, we investigated the effects of R-HDL on survival, endotoxemia, cytokine production, and pathophysiologic and metabolic events in our canine model of septic shock. At 0.5, 8, and 16 h after implantation of an E. coli-infected clot, canines received intravenous R-HDL, control lipid, or human serum albumin (HSA). Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor (TNF) and a smaller decrease in white blood cell counts than did animals treated with lipids or HSA. Survival times of lipid- or HSA-treated animals were similar and were significantly greater than those of R-HDL-treated animals. R-HDL-treated animals had significantly greater abnormalities in liver function compared with lipid- or HSA-treated animals. In normal animals, R-HDL caused transient elevation of liver enzymes, and in animals given sterile clot intraperitoneally, R-HDL caused seizures. Thus, this preparation of R-HDL had anti-endotoxin effects but also had hepatic and neurologic toxicities. We now plan to investigate a different preparation of HDL that has a different chemical composition than that used in the canine experiment. This new preparation was manufactured in such a way as to limit the potential for hepatic and neurological toxicity. We will investigate the new R-HDL preparation in small animal models of infection (rats); subsequently, if no toxicity is seen and beneficial anti-endotoxin effects are documented, we will apply it to our canine model of septic shock. If toxicities associated with R-HDL can be reduced, its anti-endotoxin effects may potentially be used prophylactically in high-risk patients or therapeutically in patients with established septic shock.